Halogen acyl derivatives of 4,4&#39;-di-aminodiphenyl sulphone



Patented Nov. 2, 1943 1 HALOGEN ACYL DERIVATIVES OF 4,4-DI- AMINODIPHENYL SULPHON E Horace A. Shonle and- Arthur M. Van Arendonk, Indianapolis, Ind., assignors to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Drawing. Original application December 1,

1941, Serial No. 421,238. Divided and this application October 31, 1942, Serial No. 464,146

4 Claims.

This application is a continuation in part of applicants copending application, Serial No. 361,585, filed October 1'7, 1940; and is a division of applicants co-pending application Serial No. 421,238, filed December 1, 1941, now Patent No. 2,323,573, granted July 6, 1943.

This invention relates to halogen acyl derivatives of chemotherapeutic agents and processes of preparing them.

Many of the compounds of this invention are particularly efi'icacious in combating streptococcal infections. For example, a dose of 4,4- di(trichloroacetylamino) diphenyl sulphone is at least as effective as 4,4'-diaminodiphenyl sulphone when administered orally or intraperitoneally to white mice in combating streptococcic infections. In addition, the compounds of this invention are markedly less toxic than the parent substances from which they are derived.

, The compositions of this invention may be represented by the following formula:

R1 H O H (l) Rr-C-C-N S N 1 R: O R:

in which R1 is a halogen selected from the class consisting of chlorine and bromine; R2 is a member of the class consisting of chlorine, bromine, and hydrogen; and R3 isa member of the class of acetyl, propionyl, and butyryl.

Throughout the description of this invention R1, R2, and R3 have the same meaning as heretofore defined. The substituents R1, R1 in Formulas 1 and 2 represent identical halogens.

(3) H o H H/ t R4 in which R4, is a member of the class consisting of acetyLpropionyl and butyryl.

The 4-amino-4'-R4-aminodiphenyl sulphone is dissolved or suspended in a suitable solvent, preferably miscible with Water, such-as dioxane, and the substituted acetyl chloride is added to the solution or suspension. Other solvents which are not miscible with water, such as ethyl acetate, may be used. The mixture is agitated, as by means of stirring, and permitted to stand for approximately one hour, within whichtime the reaction is completed and the desired compound formed. An excess of water is then added together with sufficient mineral acid, such as hydrochloric acid, to help keep in solution the unreacted or unacylated 4-amino-4-R4-aminodiphenyl sulphone. The resulting suspension is cooled until the bulk of the newly prepared material has solidified. The desired product is separated from the supernatant liquid by any suitable means, such as filtration. This precipitate may be purified by recrystallization from a solvent, such as methyl alcohol, dioxane, or glacial acetic acid. The reaction which takes place may be represented by the following equation:

. H H /H.

It is observed that the onemolecular equivalent of the amino base acts to neutralize the hydrohalogen acid which is formed. The amino base is soluble in acid, whereas the halogen acyl derivative is relatively insoluble in acid. For this reason, it is desirable to add a small quantity of a mineral acid, such as hydrochloric acid, to the reaction mixture after the reaction has been completed and the mixture has been diluted in solution in order to retain the unreacted or unacylated 4-amino-4'-R4-aminodipheny1 sulphone in solution.

Some examples of the preparation of derivatives of this invention are as follows:

EXAMPLE 1.--The preparation of 4-tribromoacetyl-amz'no-4'-acetylaminodiphenyl sulphone 5.8 g. (about 0.02-mo1) of 4-.aminos4'vaoetylamino-diphenyl sulphone are dissolved in about 100 cc. of dioxane and to this solution are added, with stirring 3.6 g. (about 0.01 mol) of tribromoacetyl bromide.

at room temperature for about. onehoun withinwhich time 4-tribromoacetylarninoAf-acetyl fi m: inodiphenyl sulphone is produced... The mixture" is then diluted with about 300 cc. 01' water, to

which about cc. of concentrated hydrochloric acid (sp. gr. 1.2) are added 4-ti'lbromoe acetyl-4'-amino-diphenyl su'lphoneseparates out as an oil or crystalline solid. To secure a larger yield and facilitate crystallization, the mixture is 20 BLO O 5) B i- -NGJiG I-gFCHWF z: W H/NOiONzlL-Qgl Exsmmn 2.The preparation, of 4-tribmmqq fi tylamino-4!,prop1onylaminodiphenyl sulpltone and 4 tribromoacetyZamino-4'-butyrylamin0- diphenyl sulphone Instead of using 4 amino-,4'-acetylaminodi+ phenyl sulphone, as'outlined in Example 1, an

equivalent amount of 4-amino-4-propionylaminodiphenyl' sulphone or-4-amino-4'-butyrylaminodiphenyl sulphonelmay be used-to produce respectively 4"-tribromoacetylamino 4'-propionyl amino iph nyl s phon QI' -=t1 b Dm0aQBhy1%m ino-4 -buty y minod nhenyl sulphone.

The 4-aminc- "-propiony aminodiph nyl su phone" mployed to p epare 4=tribromoa.cetylamino p opionylaminedinbe yl. su nhons isa new comp ndLandis preparcdms follows;

To 2 5-g. (about. 0.1lmol) of cameos.

phenyl. sulphohc dis olved. 111.200.00.91 boiling dio an are added 13 a. about 0-1 mol) f prepionic. anhydride. 'lheisolution. is. boiled; i'pr several minutes. during whic me the de i e product is formed; and then allowed toficoolto room temperature. he solu iqni thenpoil ed into L5 liters ofjwaterp nta nin .150 o y oncntrated hydro hloric. acid (so, an 1.2 and i he allqwcsltastandiicr one. h u af er. wh h time: the mant e t die n nr am n dmhen suiph ne is re o dibr' lt t T e nitrat s pa ia l neut l ed t mm n um hy r x d solution until a slight cloudiness appears, It is then chilled to below "52 (3. for preferably notless than eighthours. The precipitate which forms The ture a ita ed' for P; 10 period of fifteen minutes and is alloweditdstmdi g a) H,

consists of the desired 4-amino-4-propionylaminodiphenyl sulphone with some unchanged 4,4- diaminodiphenyl sulphone. This precipitate is dissolved in a minimum amount of boiling methyl 5 al ohol and then cooled topreie ably sl g y b low 0 C. The precipitate is filtered ofi and recrystallized ofice or twice from methyl alcohol. The 4-amino-4'-propionylaminodiphenyl sulphone melts at about 200-201 C., uncorrected, andfmay erepresented by the following formula:

The; e-aminer i'-butyrylaminodiphenyl sulphone ig'glso anew compound and is prepared in the same manner as the 4-amino-4'-propionylamimfliphenyl sulphone using 25 g. (about 0.1 mol) of 4,4'-diaminodiphenyl sulphone and 15.8

' g, (iab out (1.1 mol) otbutyric anhydride; 'I'hedes red trimm rutyrr am o iphenylsulphate melts at-about [92"493" Q, uncorrected;

'Qiusing tribromoa-cetyl-bromide. a outlined in Example 1, an equivalent amount oi t chlomacety ch oride may to produce tricbloroa etylammo acetylamiaodiphenyl sulphan 4-triphlo a e y amino 4 eac t yh aminodiphenrl su phuric h s-a melting of about 258 269 Q. unco re ted,- and may he 35 represente b e o lowins form la:

EXAMPLE 4.-1Zh eof girtrichlorgacetylamino 4' proz'nonylami ,odiphenyl sulph'one and- Hrichlorqaeetylaminowt-buturylaminodz'phenyl sulphone Exmrtr 5, lihe p eparati n pf dib rowwacctu amino-4'-acetylam.in dwhe' 1W1 $169M 5.8g. (about 0.02-niois). of t-amino-y-acetylaminodiphenyl' sulphone are dissolved in about cc. of dioxane andtothis solution are added with stirring 2.8 g. .(aboutflm mol) of dibromaacetyl bromide. The mixture is agitated for a period of l5 minutes and'is allowed to stand at room temperaturedor' about one heur, within which "time 4 dibromoacetylamino i -acetylmainodiphenyl sulphone is produced. 'rhemixture is thendiluted'wlthabout 100 carol water to which about 30 cc. of concentrated hydnov chloric acid ,(sp. gr. 1,2) are added; The dibromoacetyl aminpdiph'eqyl suiphone separates out as an oil or crystalline solid. To secure a la ger. yield. and. facilita e crys allization. e mixture i illed to less han 19 C. torabout We or threeheurs. Tbesolid precipitate is fi a es; 9 L" 'llqpluiix he. roduct, the precipitate is dissolved in boiling dioxane or other suitable solvent. The hot solution is diluted slightly with water to incipient precipitation and is cooled. The solid material which separates is 4-dibromoacetylamino 4 acetylaminodiphenyl sulphone and is represented by the following:

EXAMPLE 6.-The preparation of 4-dibromoacetylamin0-4 propionylaminodiphenyl sulphone and 4 dz'bromacetylaminoi'-butyrylamin0diphenyl sulphone Instead of using 4-amino-4'-acetylaminodiphenyl sulphone, as described in Example 5, an equivalent amount of 4-amino-4'-propionylaminodiphenyl sulphone for 4-amino-4'-butyrylaminodiphenyl sulphone may be used to produce respectively 4 dibromoacetylamino-4'-propiony1- aminodiphenyl sulphone or 4-dibromoacetylamino-4'-butyrylaminodiphenyl sulphone.

EXAMPLE 7.-The preparation of 4-dichl0roacetylamino-4'-acetylaminodiphenyl sulphone Instead of using dibromoacetyl bromide, as outlined in Example 5, an equivalent amount of dichloroacetyl chloride may be used to produce 4-dichloroacetylamino 4' acetylaminodiphenyl sulphone.

EXAMPLE 8.The preparation of 4-dichloroacetylamino 4 propionylaminodiphenyl sulphone and 4-dichloroacetylamino-4'-butyrylaminodiphenyl sulphone Instead of using 4-amino-4'-acetylamidodiphenyl sulphone, as outlined in Example 5, an equivalent amount of 4-amino-4'-propionylaminodiphenyl sulphone and 4-amino-4'-butyrylaminodiphenyl sulphone is reacted with the required amount of dichloroacetyl chloride to produce respectively 4-dichloroacetylamino-4'-propionylaminodiphenyl sulphone and 4-dichloroacetylamino-4'-butyrylaminodiphenyl sulphone.

What is claimed is:

1. A compound which is represented by the following formula:

i: i 0 H N 0 RI in which I? R-C- 

